Antioquia was until recently a genetic isolate and with the modern rapid expansion of its population this Colombian state has sustained a serious genetic burden due to the original founder effects. In particular, late onset neurodegenerative diseases have emerged at nearly epidemic proportions in several villages. Large kindreds have been characterized with genetic forms of Alzheimer's disease, Huntington's disease, Parkinson's disease, and CADASIL. Through a variety of collaborations and the persistence of Colombian scientists over many years in the face of limited resources, the responsible gene mutations are now known in all of the affected families. Many of our key insights to the global problem of neurodegeneration have stemmed from those relatively rare families with genetic forms of these diseases. Although dominant gene mutations account for less than 1% of all cases of Alzheimer's, the discovery and validation of therapeutic targets has come from genes identified in these families such as presenilin and the amyloid precursor protein (APP) gene, which were identified in familial Alzheimer's disease. As we reported in 1997 (JAMA 277:793-799), the familial Alzheimer kindred in Antioquia are the largest aggregation of this disease in the world with family trees now consisting of over 5000 individuals. This pedigree has been enormously informative and the source of an ongoing and productive collaboration between the PI and scientists at the foreign site. What has been missing from this collaboration is a sound basis at the foreign site for the execution of a laboratory-based program. In international research of this sort, too often collaborating scientists come to harvest a unique genetic resource without creating an opportunity for a talented group of local scientists to translate their own clinical and epidemiologic work into the laboratory sphere. Laboratory studies represent an essential extension to fully understand this genetic resource and to develop approaches toward treatment for a rapidly growing problem. We have designed a program that will build research capacity at the local site and possibly impact the treatment of neurodegenerative disease both in Colombia and worldwide. Work in the Kosik lab has demonstrated the feasibility of using RNAi to suppress gene expression in mammalian neurons (PNAS 99:11926-9, 2002). The scientific goals of our program are to develop RNAi approaches to 'knock-down' expression of BACE, an enzyme involved in the cleavage of APP to A-beta. We will also use a similar approach to knock-down Huntington, mutations in which lead to Huntington's disease. These experiments open the way for the Colombian scientists to participate directly in the next phase of the research beyond descriptive genetics in which the Colombian group has made such a strong contribution. [unreadable] [unreadable]